A Phase I trial combining intravenous fenretinide and safingol to target overproduction of cytotoxic dihydroceramides in malignant cells PI: Barry J. Maurer, MD PhD ABSTRACT Fenretinide (4-HPR) is a p53-independent retinoid selectively cytotoxic to cancer cells via increase of reactive oxygen species and the de novo increase of native long chain D-erythro-dihydroceramides. Safingol is L-threo- dihydrosphingosine, an artificial stereochemical variant of sphinganine, the native precursor of dihydroceramides in mammalian cells. We have shown in human and canine cancer cell lines that safingol is incorporated into long-lived, L-threo-dihydroceramides. Our preclinical data demonstrated that safingol strikingly synergized fenretinide cytotoxicity in vitro by simultaneously increasing both artificial L-threo-dihydroceramides and native D-erythro-dihydroceramides in a tumor cell-specific manner. We hypothesized that this novel, cancer-specific biochemistry might be achievable in human cancers should adequate drug levels be achievable in patient tumors in situ. Via an NCI RAID grant, we prepared novel intravenous emulsion formulations of both fenretinide and safingol suitable for high-dose delivery. Our phase I adult trials of intravenous 4-HPR demonstrated that it is well-tolerated, achieved high circulating plasma 4-HPR levels, and produced durable complete responses in T-cell lymphomas with additional signals of activity in solid tumors. A Phase I trial of our intravenous safingol formulation demonstrated that it was well-tolerated in combination with cisplatin at safingol doses believed sufficient to attain the desired dihydroceramide modulation. Our IND-directed, canine toxicology studies showed that the combination of intravenous safingol and fenretinide was well-tolerated and lacked hematopoietic toxicity within our target dosing. We now propose to conduct a phase I trial of intravenous safingol in combination with intravenous 4-HPR in adult solid tumors and lymphomas. The proposed trial will define the maximally tolerated dose (MTD) of intravenous safingol when combined with fenretinide, the pharmacokinetics of both agents in combination, obtain ancillary markers of the pharmacodynamic actions of both agents in combination by measuring plasma sphingolipid and sphingosine-1-phosphate levels, and, within the confines of a phase I trial, determine the activity of this novel drug combination. This trial is the first in man to specifically target the dihydroceramide pathway as a cytotoxic cancer treatment. If successful, this novel biochemical attack on malignant cells will constitute a broad-based, p53-independent therapy widely active in both adult and pediatric malignancies. PUBLIC HEALTH RELEVANCE: .Novel biochemical attacks on cancer cells are needed to improve clinical outcomes. The proposed Phase I study of intravenous safingol + fenretinide is a first-in-class drug combination that specifically targets the dihydroceramide pathway as a cytotoxic cancer treatment. If successful, this novel biochemistry may constitute a broad-based, p53-independent therapy widely active in both adult and pediatric malignancies and address a major unmet need.